Interrogating DNA methylation associated with Lewy body pathology in a cross brain-region and multi-cohort study

ABSTRACT Lewy body (LB) diseases are an umbrella term encompassing a range of neurodegenerative conditions all characterized by the hallmark of intra-neuronal α-synuclein associated with the development of motor and cognitive dysfunction. In this study, we have conducted a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of LB pathology. Utilizing a combined dataset of 1,217 samples across 844 unique donors, we identified a set of 24 false discovery rate (FDR) significant loci that are differentially methylated in association with LB pathology, the most significant of which were located in UBASH3B and PTAFR, as well as an intergenic locus. Ontological enrichment analysis of our meta-analysis results highlights several neurologically relevant traits, including synaptic alterations. We leverage our data to compare DNA methylation signatures between different neurodegenerative pathologies and highlight a shared epigenetic profile across LB diseases, Alzheimer’s disease and Huntington’s disease, although the top-ranked loci show disease specificity. Utilizing summary statistics from previous large-scale genome-wide association studies we identified significant enrichment of DNA methylation differences with respect to increasing LB pathology in the SNCA genomic region. We identified specific relationships between genetic risk variants for LB-Dementia and Parkinson’s disease to methylation quantitative trait loci in the promoter region and expression of SNCA transcript isoforms. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was funded by research grants from the Medical Research Council (MRC (MR/S011625/1), the National Institute of Aging (NIA) of the National Institutes of Health (NIH) (R01AG067015), the Alzheimer's Society (AS-PG-16b-012), Alzheimer's Research UK (ARUK-PG2023A-037) and the Charles Wolfson Charitable Trust to KL, research grants from the Michael J Fox Foundation (MJFF-023152) and ZonMw Memorabel/Alzheimer Nederland Grant (733050516) to EP and a research fellowship from the Alzheimer's Society (AS-PDF-23-017) to JI. Tissue for this study was provided by the Newcastle Brain Tissue Resource which is funded in part by a grant from the UK MRC (G0400074), by NIHR Newcastle Biomedical Research Centre and Unit awarded to the Newcastle upon Tyne NHS Foundation Trust and Newcastle University, and as part of the BDR Programme jointly funded by Alzheimer's Research UK and the Alzheimer's Society. The Parkinson's disease Brain Bank, at Imperial College London is funded by Parkinson's UK, a charity registered in England and Wales (258197) and in Scotland (SC037554). The Oxford Brain Bank, supported by MRC, the NIHR Oxford Biomedical Research Centre and the BDR programme, jointly funded by Alzheimer's Research UK and the Alzheimer's Society. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of University of Exeter Medical School Research (13/02/009) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Analysis alterations following feedback, including additional sensitivity analyses controlling for Thal stage, additional SNCA QTL investigation added. Additional sample exclusion ammended and results throughout manuscript updated accordingly. Section on predictor models removed as decided as out of scope of this report. Additional supporting coauthors added and affiliations ammended Data Availability Methylation data, genotyping data and available phenotypic data used in primary analyses for the UK Brain Bank Network cohort will be made available on the Gene Expression Omnibus (GEO) Platform upon peer review and final publication. Data for the Netherlands Brain Bank cohort is available via GEO at accession number GSE203332. Data for the Brains for Dementia Research cohort is available via GEO at accession number GSE197305 and additional donor data is available via Dementia Platform UK (https://portal.dementiasplatform.uk/). Genome-wide summary statistics for meta-analyses performed in this study are available at https://github.com/JoshHarveyGit/LB_Meta_Analysis. DATA AVAILABILITY Methylation data, genotyping data and available phenotypic data used in primary analyses for the UKBBN cohort will be made available on the Gene Expression Omnibus (GEO) Platform upon final publication. Data for the NBB cohort is available via GEO at accession number GSE203332. Data for the BDR cohort is available via GEO at accession number GSE197305 and additional donor data is available via Dementia Platform UK (https://portal.dementiasplatform.uk/). Genome-wide summary statistics for meta-analyses performed in this study are available at https://github.com/UoE-Dementia-Genomics/LB-Meta-Analysis